Synthesis and Preliminary Biological Evaluation of Two Fluoroolefin Analogs of Largazole Inspired by the Structural Similarity of the Side Chain Unit in Psammaplin A

Abstract

Largazole, isolated from a marine Cyanobacterium of the genus Symploca, is a potent and selective Class I HDAC (histone deacetylation enzymes) inhibitor. This natural 16-membered macrocyclic depsipeptide features an interesting side chain unit, namely 3-hydroxy-7-mercaptohept-4-enoic acid, which occurs in many other natural sulfur-containing HDAC inhibitors. Notably, one similar fragment, where the amide moiety replaces the trans alkene moiety, appears in Psammaplin A, another marine natural product with potent HDAC inhibitory activities. Inspired by such a structural similarity, we hypothesized the fluoroolefin moiety would mimic both the alkene moiety in Largazole and the amide moiety in Psammaplin A, and thus designed and synthesized two novel fluoro olefin analogs of Largazole. The preliminary biological assays showed that the fluoro analogs possessed comparable Class I HDAC inhibitory effects, indicating that this kind of modification on the side chain of Largazole was tolerable.

Unexpected Enhancement of HDACs Inhibition by MeS Substitution at C-2 Position of Fluoro Largazole

“…For example, fixing fluorine at C18 position of the linker could keep almost the same inhibitory activity and selectivity of HDACs. Subsequently, the replacement of Val with Phe gave slightly reduced inhibition of HDACs, similar to the previous observations reported for largazole [23]. As our research continued, we discovered to our surprise that the replacement of Val with S-Me Cys significantly enhanced the inhibition of HDACs, whereas the replacement with Gly significantly decreased the activity.…”

“…In our previous paper [23], we synthesized the two fluoroolefin analogs of largazole with Val and Phe residue at C2 position. The key macrolactamization was chosen at N2 position, but the yields were poor (less than 31% yield).…”

“…All these works indicated that the structural optimization at the C2 position appeared not to improve the potency of HDACs inhibition. Recently, we discovered that the modification on the linker of largazole was allowable in some cases (Figure 1) [22][23][24]. For example, fixing fluorine at C18 position of the linker could keep almost the same inhibitory activity and selectivity of HDACs.…”

“…With an expanded research program under way based on this observation, we would like to communicate here our preliminary results and provide rational explanation for the unexpected results through a molecular modeling study. To the best of our knowledge, the S-Me Cys Recently, we discovered that the modification on the linker of largazole was allowable in some cases ( Figure 1) [22][23][24]. For example, fixing fluorine at C18 position of the linker could keep almost the same inhibitory activity and selectivity of HDACs.…”

Design, Synthesis and Biological Evaluation of Jahanyne Analogs as Cell Cycle Arrest Inducers

“…Moreover, these products exhibit diverse biological activities, ranging from anticancer to antibiotic activity [5][6][7][8]. The discovery of dolastatin-10 [9], cryptophycin-52 [10], and largazole [11] from marine cyanobacteria, and their clinical analogs for cancer therapy, highlights the powerful potential of marine cyanobacteria as a pool for drug discovery [12]. An intriguing lipopeptide-type class from marine cyanobacteria, including dragonamide [13], kurahyne [14], viridamides [15], carmabin A [16], almiramides [17], and jahanyne ( Figure 1) [18], is heavily N-methylated.…”